Primary infection with varicella-zoster virus (VZV) causes chickenpox, and reactivation of the virus from latency results in zoster. The purpose of this project is to study the molecular pathogenesis and latency of VZV and to identify targets for novel therapies. We have found that the major VZV gene expressed during latency, ORF63, is not required for replication of virus in cell culture. Infection of rodents with a virus that is deleted for ORF63 showed that the VZV mutant is able to enter the nervous system; however, the virus is unable to efficiently persist in the nervous system and establish latency. Additional viruses with different mutations in ORF63 demonstrate that mutants that are impaired for growth in cell culture are also impaired for latency, while a mutant that does not show reduced growth in cell culture is not impaired for latency. We identified a small region of the ORF63 gene that is important for both replication and latency. We have also constructed a mutant VZV that is deleted for ORF4, another VZV gene that is expressed during latency. This virus is unable to grow in cell culture unless grown on a complementing cell line and is severely impaired for establishment of latency in rodents. Derivatives of these viruses might be improved vaccine candidates since they are impaired for latency and should be less likely to reactivate. We have shown that VZV infects and replicates in immature dendritic cells. These cells are important for processing viral proteins and for presenting these proteins to the cellular arm of the immune system. We found that one VZV gene, ORF47, is required for efficient virus replication in these cells and for spread of virus from dendritic cells to other cells. VZV with a mutation in the ORF47 gene is able to enter dendritic cells and express virus early genes; however, very little late virus gene expression occurs. We also found that VZV infection of dendritic cells resulted in down-regulation of a protein (Fas) on the surface of the cells that is important for programmed cell death, and for defense of cells against virus infection.